This research is concerned with comparative studies of the major histocompatibility complex (MHC) in inbred and wild Norway rat populations. We have previously demonstrated that the genetic loci in the RT1 complex that control the expression of serologically defined histocompatibility and Ia antigens, the mixed lymphocyte response, and the immune response to synthetic polypeptide antigens are much less polymorphic than expected. In addition, these different loci in random populations exhibit high degrees of linkage disequilibrium, suggesting that selective pressures are preferentially influencing the retention of selected MHC haplotypes. In the past year the experimental work supported by this grant has focused on the functional and structural characteristics of the rat MHC. We have: (1)\biochemically isolated and characterized the gene products of two class II loci, RT1.B and RT1.D, and demonstrated their homology to comparable loci in the mouse; (2)\established the immune response profile to simple antigens and tentatively assigned the Ir control for poly(Glu53Lys53Tyr15) and lactic dehydrogenase to RT1.Dand the response to bovine insulin to RT1.B; (3)\conducted a series of experiments demonstrating the relative importance of MHC versus non-MHC genes in allograft rejection of skin, heart and bone marrow; and (4)\documented the existence in the rat MHC of a locus that codes for the quantitative expression of a serum protein immunochemically identical or very similar to the C4 complement component of the mouse. Much of this work was made possible because of new genetic variants of the MHC isolated from the wild and maintained in our rat colony.